| Summary: | 碩士 === 高雄醫學大學 === 醫學研究所 === 88 === ABSTRACT
KMUP-1, a new xanthine derivative, was first investigated under in vivo and in vitro models. KMUP-1 (1.0, 3.0, 5.0 mg/kg) caused a long lasting dose-dependent hypotensive effect for above 2 hours and had a mild short-acting bradycardic effect in pentobarbital-anesthetized Wistar rats. Both bradycardiac and hypotensive effects of KMUP-1 (1.0, 3.0, 5.0 mg/kg, i.v.) were markedly inhibited by pretreatment with glibenclamide (5 mg/kg, i.v.), a specific ATP-sensitive potassium (KATP) channels blocker. In phenylephrine-preconstricted endothelium—intact or denuded rat and rabbit aortic rings, KMUP-1 produced a concentration-dependent relaxation. KMUP-1-induced aortic relaxation was reduced by endothelium removed or by the presence of L-NAME (100 mM), a nitric oxide synthase inhibitor. In addition, the vasorelaxant effects of KMUP-1 were inhibited by pretreatment with soluble guanylyl cyclase inhibitors methylene blue (10 mM) and ODQ (1 mM), a K+ channels blocker TEA (10 mM), a KATP channels blocker glibenclamide (1 mM), a votage-dependent potassium channels blocker 4-aminopyridine (4-AP, 100 mM), and adenosine receptor antagonists 3,7-dimethyl-1- propargylxanthine (DMPX, 10 mM), 8-(3-chlorostyryl)caffeine (CSC, 10 mM) and alloxazine (10 mM). Moreover, increased extracellular potassium levels (30-80 mM) resulted in concentration-dependent attenuation of the vasodilator effects of KMUP-1. Preincubation with KMUP-1 (10-8~10-6 M) significantly increased the maximal dilator responses mediated by endogenous NO in aortic rings that was released upon exposure to acetylcholine, and enhanced the dilator response to the exogenous NO-doner SNP. In thoracic aorta experiments, KMUP-1 competitively antagonized the norepinephrine-induced vasocontration in a concentraction-dependent manner. The parallel shift to the right of the concentration-response curve of norepinephrine suggested that KMUP-1 was a α-adrenoceptor competitive antagonist. On the other hand, we found that the vasorelaxant effects of KMUP-1 (10, 50, 100 nM) together with IBMX (500 nM) had an additive action. In isolated guinea-pig atria, KMUP-1 produced negative inotropic and chronotropic activities. The effects of KMUP-1 were significantly antagonized by pretreatment with TEA, glibenclamide, 4-AP, methylene blue, ODQ, 8-PT and methocramine. KMUP-1 also elicited concentration-dependent relaxant responses in carbachol-contracted guinea-pig tracheal smooth muscle. The responses of KMUP-1 were inhibited by TEA, 4-AP, methylene blue, ODQ, DMPX, CSC and alloxazine. However, pretreatment with SQ 22536, theophylline, glibenclamide and an adenosine A1 receptor antagonist 8-PT were no significant inhibition on the effects induced by KMUP-1. The vasorelaxant effects of KMUP-1 (10, 50, 100 nM) together with IBMX (500 nM) had an additive action only at high concentration. In isolated rabbit corpus cavernosal smooth muscle preconstricted by phenylephrine (10 mM), KMUP-1 (1 nM~100 mM) produced a concentration-dependent relaxation. The relaxant effects of KMUP-1 were inhibited by pretreatment with TEA, glibenclamide, 4-AP, methylene blue and ODQ. KMUP-1 induced a concentration-dependent increase in intracellular cyclic GMP levels in rat aortic rings. The cyclic GMP content of KMUP-1 (0.1~100 mM) was nearly inhibited completely by methylene blue (10 mM), L-NAME (100 mM) and ODQ (10 mM). Furthermore, the binding characteristics of KMUP-1 were evaluated in [3H]DPCPX biding to rat cortex, [3H]CGS 21680 binding to striatum and [3H]prazosin binding to brain membranes. The above results indicated that KMUP-1 is a unique xanthine derivative by the activation of adenosine receptor and antagonism of a-adrenoceptors, and its smooth muscle relaxation effect might be mediated by the stimulation of NO/sGC/cGMP pathway and opening the K+ channels.
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